2WTK

Structure of the heterotrimeric LKB1-STRADalpha-MO25alpha complex

Summary for 2WTK

• Entry DOI: 10.2210/pdb2wtk/pdb
• Related: 1UPK 1UPL
• Descriptor: CALCIUM-BINDING PROTEIN 39, STE20-RELATED KINASE ADAPTER PROTEIN ALPHA, SERINE/THREONINE-PROTEIN KINASE 11, ... (6 entities in total)
• Functional Keywords: transferase-metal-binding protein complex, transferase metal-binding protein complex, kinase, nucleus, serine/threonine-protein kinase, pseudokinase, phosphoprotein, signal transduction, transferase, nucleotide-binding, transferase/metal-binding protein
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm (Potential): Q9Y376; Nucleus: Q7RTN6 Q15831
• Total number of polymer chains: 6
• Total formula weight: 234063.08

Authors

Zeqiraj, E.,van Aalten, D.M.F. (deposition date: 2009-09-16, release date: 2009-12-15, Last modification date: 2023-12-20)

Primary citation

Zeqiraj, E.,Filippi, B.M.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F.
Structure of the Lkb1-Strad-Mo25 Complex Reveals an Allosteric Mechanism of Kinase Activation.
Science, 326:1707-, 2009

PubMed Abstract: The LKB1 tumor suppressor is a protein kinase that controls the activity of adenosine monophosphate-activated protein kinase (AMPK). LKB1 activity is regulated by the pseudokinase STRADalpha and the scaffolding protein MO25alpha through an unknown, phosphorylation-independent, mechanism. We describe the structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation. STRADalpha adopts a closed conformation typical of active protein kinases and binds LKB1 as a pseudosubstrate. STRADalpha and MO25alpha promote the active conformation of LKB1, which is stabilized by MO25alpha interacting with the LKB1 activation loop. This previously undescribed mechanism of kinase activation may be relevant to understanding the evolution of other pseudokinases. The structure also reveals how mutations found in Peutz-Jeghers syndrome and in various sporadic cancers impair LKB1 function.

PubMed: 19892943
DOI: 10.1126/SCIENCE.1178377

Experimental method

X-RAY DIFFRACTION (2.65 Å)